Available online at www.ijpcr.com International Journal of Pharmaceutical and Clinical Research 2012; 4(4): 77-80 ISSN 0975 1556 Research Article
Design and Characterization of Ranitidine Hydrochloride Floating Tablets by Wet Granulation Method *K.NagaRaju, Duraivel.S, Pragath Kumar.B Department of Pharmaceutics, Nimra College of Pharmacy, Vijayawada-521456 ABSTRACT Currently there are a number of technologies available that have been used to provide sustained release dosage forms and some of these involve the use of a wide range of polymers. This present research describes an investigation of the effects of formulation and processing parameters on a floating matrix controlled drug delivery system consisting Methods: The tablets were prepared by Wet granulation process using Ranitidine hydrochloride, HPMC K-4M ,Carbopol ,sodium carboxy methyl cellulose ,Guar Gum ,Xanthan gum ,sodium bicarbonate ,citric acid ,Stearic acid ,Hydrochloric acid ,Talc ,Mag.Stearate. The physicochemical properties like thickness, hardness, Weight variations, Friability, Drug content, Floating log time, Swelling Index etc were determined. The In-Vitro drug release rate of floating tablets was determined using United States Pharmacopeia Dissolution Testing Apparatus 2 (paddle method). The dissolution test was performed using 900 ml of 0.1N HCL, at 37 ± 0.5°C and 50 rpm. A sample (5 mL) of the solution was withdrawn at 1,2,3,4, up to 12hrs from and the samples were replaced with fresh dissolution medium. The samples were filtered. Through a 0.45μ membrane filters and diluted to a suitable concentration with 0.1N HCL. Absorbance of these solutions was measured using a UV- spectrophotometer and the stability studies were conducted for a period of three months Conclusion: It was established that formulation R11 (360 minutes) has better in vitro release profiles in comparison to the commercial product. The result obtained is encouraging, because a longer gastric residence time is an important condition for higher bioavailability of the drugs included in the floating dosage forms. Hence Ranitidine HCL floating tablets could be promising one as they, minimizes the dose, and reduces the side effects. Key words: Ranitidine, Hydrochloride, Wet Granulation Method. release the Drug slowly into the gastrointestinal tract and INTRODUCTION Oral administration is the most convenient and preferred maintain an effective drug concentration in the systemic means of any drug delivery. Oral controlled release drug circulation for a long time. After oral administration, such delivery have recently been of increasing interest in a drug delivery would be retained in the stomach and pharmaceutical field to achieve improved therapeutic release the drug in a controlled manner, so that the drug advantages, such as ease of dosing administration, patient could be supplied continuously to its absorption sites in compliance and flexibility in formulation. the gastrointestinal tract. Drugs that are easily absorbed from gastrointestinal tract (GIT) and have short half-lives are eliminated quickly MATERIALS AND METHODS from the systemic circulation. Frequent dosing of these Materials: The following chemicals like Ranitidine drugs is required to achieve suitable therapeutic activity. hydrochloride, HPMC K-4M ,Carbopol ,sodium carboxy To avoid this limitation, the development of oral methyl cellulose ,Guar Gum ,Xanthan gum ,sodium sustained-controlled release formulations is an attempt to bicarbonate ,citric acid ,Stearic acid ,Hydrochloric acid Table 1: Composition of Floating Tablets Containing Ranitidine HCL. S. INGREDIE R1 R2 R3 R4 R5 R6 R7 R8 R9 R10 R11 R12 R13 N NTS (mg) (mg) (mg) (mg) (mg) (mg) (mg) (mg) (mg) (mg) (mg) (mg) (mg) o 1. Drug 150 150 150 150 150 150 150 150 150 150 150 150 150 2 HPMC-K4M 150 100 75 50 100 75 50 100 75 50 100 75 50 3 Carbopol934 50 75 100 4 SCMC 100 75 50 5 Guar gum 100 75 50 6 Xanthan 100 75 50 gum 7 NaHCO3 50 50 50 50 50 50 50 50 50 50 50 50 50 8 Citric acid 20 20 20 20 20 20 20 20 20 20 20 20 20 9 Mag.Stearate 4 4 4 4 4 4 4 4 4 4 4 4 4 10 Talc 4 4 4 4 4 4 4 4 4 4 4 4 4 11 Stearic acid 5 5 5 5 5 5 5 5 5 5 5 5 5 In all formulations (2%) HPMC solution was used as granulating agent except CP.
Author for correspondence: Email:
[email protected]
K.NagaRaju et.al./ Design and Characterization…
R1 R2 R3 R4 R5 R6 R7 R8 R9 R10 R11 R12
3.97±0.05 3.92±0.1 4.03±0.05 3.95±0.05 3.93±0.1 4.12±0.06 4.05±0.05 3.98±0.05 4.06±0.05 4.01±0.05 4.03±0.03 3.96±0.04
5.25±0.15 5.66±0.24 5.9±0.32 6.3± 0.18 5.4±0.25 5.6 ± 0.26 5.8±0.36 5.6±0.22 5.9±0.12 6.7 ± 0.35 5.5±0.2 5.8±0.45
0.45±0.10 0.51±0.08 0.34±0.12 0.26±0.10 0.36±0.04 0.31±0.07 0.21±0.05 0.28±0.08 0.38±0.15 0.31±0.14 0.29±0.12 0.36±0.09
Weight variation (mean±SD) (mg) 398.19±2.94 391.18±3.77 402.33±1.50 398.30±3.30 394.13±3.10 403.16±2.33 404.18±1.11 397.04±2.56 401.39±1.14 398. 43±2.70 400.63±1.29 397.21±2.56
Fig 1 FT-IR of the drug and exiecpients ,Talc ,Mag.Stearate were used. Method: Granules were prepared by using wet granulation technique. All the ingredients were weighed (Stearic acid, citric acid, sodium bicarbonate and
Floating Lag Time (mean±SD) (sec) 260±10 310 ±5.7 370±10 410±10 290±10 280±5.7 330±10 280±6.8 310±10 290±5.7 290±10 260±5.7
Hausner’s ratio (mean±SD) 1.21±0.01 1.47±0.02 1.44±0.03 1.19±0.01 1.18±0.02 1.22±0.01 1.23±0.04 1.4±0.01 1.123±0.02 1.12±0.01 1.174±0.01 1.2±0.02 1.26±0.01
Swelling index (mean±SD)
Drug content (mean±SD)
175±0.15 207.5±0.15 192.5±0.18 184±0.11 279±0.17 262.5±0.13 300±0.16 289±0.14 265 ±0.19 345±0.11 341±0.17
98.33±0.92 99.20±0.34 98.19±0.55 97.60±0.39 98.21±0.07 98.14±0.69 99.52±0.81 98.34±0.65 97.71±0.92 97.34±0.37 99.25±0.1 98.34±0.2
Polymer) and taken in to motor. Finally the active ingredient was mixed homogeneously according to geometric proportions. (2%) HPMC solution acts as
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Table 3; Physiochemical properties of the tablet F.CODE Thickness Hardness Friability (mean±SD) (mean±SD) (mean±SD) (mm) (kg)
FLOW PROPERTIES Angle of repose Carr’s index (mean±SD) (mean±SD) 29.73±0.01 17.65±0.01 40.6±0.03 31.73±0.01 39.47±0.04 30.63±0.02 34.18±0.01 15.97±0.01 29.36±0.05 15.4±0.01 28.21±0.02 16.81±0.01 27.26±0.04 18.73±0.01 34.11±0.01 28.63±0.03 30.69±0.03 11.01±0.02 24.51±0.01 10.75±0.01 27.9±0.05 14.86±0.01 29.74±0.01 16.75±0.02 30.91±0.02 21.17±0.01
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Table 2: Flow property of the Blend DERIVED PROPERTIES F.CODE Bulk density Tapped density (mean±SD) (mean±SD) R1 0.294±0.01 0.357±0.04 R2 0.4545±0.03 0.666±0.03 R3 0.385±0.01 0.555±0.01 R4 0.4±0.02 0.476±0.03 R5 0.313±0.01 0.370±0.01 R6 0.334±0.04 0.41±0.02 R7 0.3125±0.03 0.385±0.02 R8 0.476±0.01 0.666±0.01 R9 0.364±0.02 0.409±0.04 R10 0.357±0.01 0.4±0.03 R11 0.567±0.04 0.66±0.01 R12 0.333±0.01 0.4±0.04 R13 0.458±0.02 0.581±0.03
K.NagaRaju et.al./ Design and Characterization… Table 4; percentage drug release FORMULATION R1 R2 R3
%DRUG RELEASE 92.5 94.6 95.2
R4 R5 R6
90.1 92.5 89.9
R7 R8 R9 R10 R11 R12
87.7 89.3 87.4 85.3 91.2 96.7
Comparative Studies for R1-R7 Formulations
IN VITRO DRUG RELEASE STUDIES OF RANITIDINE HCL (R1-R7 )
Cumulative % drug release
100 80 60 40 20 0 0
1
R1
2
3
4
R2
5
R3
6
7
Time in h R4
8 R5
9
10 11 12 R6
R7
Fig 2; percentage drug release of batch 1-7
Cumulative % drug release
IN VITRO DRUG RELEASE STUDIES OF 100 RANITIDINE HCL (R8-R13) 80 60 40 20 0 0 1 2 3 4 5 Time 6 7in h8 9 10 11 12 R8
R9
R10
R11
R12
R13
60°C 85%RH (mean±SD) 5.8±0.1
2 3
Drug content (%) floating lag time (sec)
99.25±0.1
98.5±0.3
97.3±0.5
96.7±0.7
290±5.7
300±10
310±5.7
310±10
4 Invitro Buoyancy >24 h >24 h granulating agent. The coherent mass was thoroughly sieved through 16 meshes and then dried in hot air oven at 50ºC for 45 min. The dried granules were passed through sieve no 20 to get uniform granules. To this calculated amount of Magnesium Stearate (1%) and Talc (1%) were added as a lubricant. Citric acid and sodium bicarbonate were incorporated as a gas-generating agent. The addition of Stearic acid reduces the drug dissolution due to its hydrophobic nature. Then the prepared granules
>24 h >24 h were evaluated in the following parameters bulk density, tapped density, angle of repose, compressibility index and Hauser’s ratio. Evaluation of tablet: Thickness, Hardness, Weight variation, Friability, Drug content Floating log time, Swelling index etc dissolution as per USP has been evaluated and the results has been tabulated in table in table 2.
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Table No 5: Stability study (25°C, 40°C and 60°C) of best Formulation (R11). S.No Parameters Initial 3rdMonth 25°C 60%RH 40°C 75% RH (mean±SD) (mean±SD) 1 Hardness (kg/cm2) 5.5±0.2 5.2±0.1 5.7±0.3
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Fig 3:Comparative Studies for R7-R13 Formulations
K.NagaRaju et.al./ Design and Characterization…
REFERENCES 1. Streubel A, Siepmann J, Bodmeier R. Gastroretentive drug delivery system. Expert Opin Drug Deliv. 2006; 3(2): 217- 233. 2. Ross and Wilson. Anatomy and physiology in health and illness. 9th Edition. Church chill Livingstone. 2002; 295-299. 3. Wison C.G, Washington N. In physiological pharmaceutics Biological barrier to drug absorption, Ellis Horwood Series in pharmaceutical Technology, 47. 4. Ramesh R, Putheti, Mahesh C, Patil, Pharmaceutical Formulation and development of Floating and Swellable sustained drug delivery systems: a review. e-Journal of Science & Technology. April 2009; 4 (2): 1-12. 5. Fell J.T. Targeting of drugs and delivery systems to specific sites in the gastrointestinal tract. J. Anat. 1996; 189: 517–519. 6. Talukder and Fassihi R. Gastroretentive Delivery Systems A Mini Review. Drug Development and Industrial Pharmacy. 2004; 30 (10): 1019–1028. 7. Rouge N, Buri P. Drug absorption sites in the gastrointestinal tract and dosage forms for site specific delivery. Int j pharm. 1996; 136: 117-139. 8. Singh B.N, Kim K.H. Floating drug delivery systems: an approach to oral controlled drug delivery via gastric retention.J.Control.Release.2000; 63:235-239. 9. Arora S, Khar R.K. et al., Floating drug delivery System: A Review. AAPS Pharm Sci Tech. 2005; 06(03): E372-E390. 10. Deshpande A.A, Shah N.H. Development of a novel controlled-release system for gastric retention. Pharm Res. 1997; 14: 815-819.
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CONCLUSIONS The present study was aimed at developing an oral floating system for Ranitidine HCL using combination of polymers like HPMC, CP, SCMC, Guar gum and Xanthan gum the floating tablets were prepared by using wet granulation technique. The floating tablets of Ranitidine HCL were evaluated for physicochemical characteristics like thickness, hardness, weight variation, friability, drug content, floating lag time and swelling index. The in-vitro buoyancy studies, in-vitro drug release studies. The optimized formulation R11 was compared with marketed product and the results were found that the optimized formulation R11 (360 minutes) has better in vitro release profiles in comparison to the commercial product. The result obtained is encouraging, because a longer gastric residence time is an important condition for higher bioavailability of the drugs included in the floating dosage forms. Hence Ranitidine HCL floating tablets could be promising one as they, minimize the dose, and reduces the side effects.
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RESULT AND DISCUSSION Thickness: The floating tablets showed thickness in the range of 3.91±0.02 - 4.12±0.06 mm and no significance difference in the weight of individual formulations. From the average value was observed and variations within the limits and are given in table 3 Hardness: The difference in the hardness did not affect the release of the drug from hydrophilic matrices which is 5.25±0.15 - 6.7 ± 0.35 kg/cm2 released by diffusion through the gel layer and/or erosion of this layer and is independent of the dry state of the tablet the values are given in table 3 Weight variation: The floating tablets Weight variation showed in the range of 391.18±3.77 - 404.18±1.11mg and no significance difference in the weight of individual formulations. From the average value was observed and variations within the limits and are tabulated in table 3 Friability: Tablet strength was tested by Roche Friabilator. The friability of all formulations in limits (below 1%). The friability of all formulations were observed within the range of 0.21±0.05 - 0.51±0.08 and the results are tabulated in table 3 Drug content: The drug content of all formulations was observed within the range of 97.34±0.37 - 99.52±0.81 % the values are given in table 3 Floating log time: The floating log time among all formulations were observed in the range of 260±5.7 410±10 sec and the values are given in table 3 Swelling index: Swelling index of floating tablets showed significant differences in their swelling index. The swelling indexes of all formulations were observed within the range of175±0.15-345±0.11 the values are given in table 3 Drug –Polymer Compatibility Studies By Ftir: Drug polymer compatibility studies were performed by FTIR (Fourier transform infrared spectroscopy). FTIR absorption spectra of Ranitidine, HPMC, CP, SCMC, Guar gum, Xanthan gum and the combination of drug and polymers were shows no significant interaction between Ranitidine and polymer .which is given in figure 1 In- vitro drug release studies: The release rate of floating tablets was determined using United States Pharmacopeia Dissolution Testing Apparatus 2 (paddle method). The dissolution test was performed using 900 ml of 0.1N HCL, at 37 ± 0.5°C and 50 rpm. A sample (5 mL) of the solution was withdrawn at 1,2,3,4, up to 12hrs from and the samples were replaced with fresh dissolution medium. The samples were filtered. Through a 0.45μ membrane filters and diluted to a suitable concentration with 0.1N HCL. Absorbance of these solutions was measured using a UV- spectrophotometer. The percentage drug release is given in table no 4 Stability studies: The stability study was carried out using the best batch. The stability of the tablets were characterized for hardness, drug content, floating lag time, and In vitro Buoyancy. Formulation was kept at various temperatures that are 25°C, 40°C and 60°C for three months. The amount of drug was detected UVSpectrophotometrically at 314 nm.
